denifanstat (TVB-2640) / Sagimet Biosci, Ascletis - LARVOL DELTA

Ascletis Announces Phase III Trial of Denifanstat (ASC40), a First-in-Class, Once-Daily Oral FASN Inhibitor for Acne, Meets All Endpoints (PRNewswire) - P3 | N=480 | NCT06192264 | Sponsor: Ascletis Pharmaceuticals Co., Ltd. | "Ascletis Pharma Inc...meets all primary, key secondary, and secondary endpoints in the Phase III clinical trial for the treatment of moderate to severe acne vulgaris (NCT06192264)...At week 12, percent treatment success was 33.2% compared to 14.6% for placebo, p<0.0001, percent reduction from baseline in total lesion count was 57.4% compared to 35.4% for placebo, p<0.0001, and percent reduction from baseline in inflammatory lesion count was 63.5% compared to 43.2% for placebo, p<0.0001. The key secondary endpoint, percent reduction from baseline in non-inflammatory lesion count at week 12, was 51.9% compared to 28.9% for placebo, p<0.0001...Denifanstat demonstrated a favorable safety and tolerability profile following 12 weeks of once-daily oral administration at 50 mg....'We are excited to be submitting this innovative treatment with the China National Medical Products Administration (NMPA) soon'."

P3 data: top line • Acne Vulgaris

Sagimet Biosciences to Host Virtual KOL Event, “Evaluating the Synergistic Potential of a Combination of Denifanstat and Resmetirom for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis (MASH)” on May 29, 2025 (GlobeNewswire) - "The event will provide an overview of the planned Phase 1 pharmacokinetic clinical trial of the denifanstat and resmetirom combination, and a discussion on the potential benefits of combination therapy to treat patients living with advanced MASH."

Clinical • Metabolic Dysfunction-Associated Steatohepatitis

ASC4OPT STUDY: HIGH EFFICACY AND FAVORABLE TOLERABILITY OF ASCIMINIB ONCE OR TWICE DAILY IN CML PATIENTS WITH SUBOPTIMAL RESPONSE, RESISTANCE OR INTOLERANCE OF 2 OR MORE TYROSINE KINASE INHIBITORS (EHA 2025) - P3 | "Pts were randomized 1:1 to receive ASC 40 mg BID or 80 mg QD. The ASC4OPT findings strengthen those of the ASCEMBL study, supporting ASC as a standard of care for pts with CML-CP pretreated with ≥2 TKIs; the more convenient 80 mg QD regimen may enhance treatment adherence and ultimately improve patient outcomes. Pts who discontinued previous TKIs due to intolerance were able to maintain or deepen responses on ASC regardless of dosing schedule."

Clinical • Cardiovascular • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology

FASCINIT: A Phase 3 Study Evaluating the Safety and Efficacy of Denifanstat in Patients With MASLD and MASH (clinicaltrials.gov) - P3 | N=0 | Withdrawn | Sponsor: Sagimet Biosciences Inc. | N=2000 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

FASCINATE-3: A Phase 3 Study Evaluating the Safety and Efficacy of Denifanstat in Patients With MASH and F2/F3 Fibrosis (clinicaltrials.gov) - P3 | N=0 | Withdrawn | Sponsor: Sagimet Biosciences Inc. | N=1260 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Sagimet Biosciences Reports First Quarter 2025 Financial Results and Provides Corporate Updates (GlobeNewswire) - "Phase 1 clinical trial to evaluate the PK and tolerability of a combination of denifanstat and resmetirom, planned to initiate in the second half of 2025, with an anticipated data readout in the first half of 2026....Ascletis BioScience Co. Ltd. (Ascletis) announced completion of enrollment of 480 patients in its Phase 3 clinical trial of denifanstat for acne in China, and that it expects to announce topline results in the second quarter of 2025. First-in-human Phase 1 clinical trial of TVB-3567 in acne expected to initiate in the second half of 2025, following the IND clearance in March 2025."

New P1 trial • P1 data • P3 data: top line • Acne Vulgaris • Metabolic Dysfunction-Associated Steatohepatitis

Sagimet Biosciences Announces Upcoming Presentations at EASL Congress 2025 (GlobeNewswire) - "Sagimet Biosciences...today announced that three poster presentations featuring additional analyses from the Phase 2b FASCINATE-2 study of denifanstat in MASH will be presented at the European Association for the Study of Liver (EASL) Congress 2025 being held May 7-10, 2025 in Amsterdam, Netherlands."

P2b data • Retrospective data • Metabolic Dysfunction-Associated Steatohepatitis

Structure, dynamics and therapeutic potential of fatty acid synthase (AACR 2025) - "The modifying region of hFASN was determined at near-atomic resolution using a recombinant expression system bound to the first-in-class inhibitor Denifanstat, enabling structure-based small molecule discovery...These modifications may play a role in protein stabilization or regulation under stress conditions, highlighting a potential mechanism for hFASN activity modulation. Together, these findings provide critical structural and regulatory insights, paving the way for targeted therapeutic development."

Breast Cancer • Oncology • Solid Tumor • FASN

Denifanstat improves multiple qFibrosis-based collagen features linked to major adverse liver outcomes in patients with metabolic dysfunction-associated steatohepatitis patients and high polygenic risk (EASL 2025) - No abstract available

Adverse events • Clinical • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Denifanstat improves multiple qFibrosis-based collagen features linked to major adverse liver outcomes in patients with metabolic dysfunction-associated steatohepatitis patients and high polygenic risk (EASL 2025) - P2 | "Digital pathology showed antifibrotic effect of DENI in qFibrosis-based collagen features previously linked to MALO and recapitulated NASH-CRN fibrosis staging. Pronounced changes were seen with DENI in the difficult-to-treat population with several risk variants associated with MALO. Further research is warranted to discern the specific effect related to DENI mechanism of action within the polygenic risk population."

Adverse events • Clinical • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • FASN • PNPLA3

Hepatoprotective effects of fatty acid synthase inhibitor TVB-3664 in the GAN diet-induced obese and biopsy-confirmed mouse model of MASH (EASL 2025) - "Background and Aims: Denifanstat, an oral fatty acid synthase (FASN) inhibitor, have recently been demonstrated to improve NAFLD Activity Score (NAS) and fibrosis stage in a phase 2b clinical trial (FASCINATE-2) in patients with metabolic dysfunction-associated steatohepatitis (MASH). TVB-3664 improved metabolic, biochemical and histological markers of steatosis, inflammation and fibrosis/fibrogenesis. In addition, TVB-3664 improved histopathological NAFLD Activity Score, with longer treatment intervention needed for fibrosis stage improvement. The therapeutic effects of TVB-3664 highlight the translatability and applicability of the GAN DIO-MASH mouse model in preclinical drug discovery."

Biopsy • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • FASN

Preclinical characterization of BJT-188, a liver-targeted fatty acid synthase inhibitor for the treatment of MASH (EASL 2025) - "The first-generation FASN inhibitor Denifanstat reduces liver steatosis, inflammation, and fibrosis in MASH patients... BJT-188 is a potent and selective FASN inhibitor with high liver-to-plasma partitioning and low potential for alopecia. BJT-188 is currently progressing towards IND enabling studies."

Preclinical • Alopecia • Fibrosis • Immunology • Inflammation • Metabolic Dysfunction-Associated Steatohepatitis • FASN

Denifanstat-mediated reduction of plasma glycine- and taurine-conjugated bile acids correlates with histological improvements in denifanstat-treated metabolic dysfunction-associated steatohepatitis patients in phase 2b FASCINATE-2 study (EASL 2025) - "Identifying reliable biomarkers for response prediction is crucial for advancing precision medicine. In MASH patients treated with denifanstat, glycine- and taurine- conjugated bile acids were significantly reduced at 26 weeks in histological responders for both fibrosis regression and MASH resolution, suggesting that this could potentially be leveraged as a response biomarker in patients treated with denifanstat."

Clinical • P2b data • Diabetes • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Type 2 Diabetes Mellitus

Assessment of the metabolic dysfunction-associated steatohepatitis resolution index and component biomarkers in prediction of histology response to denifanstat in the FASCINATE-2 trial (EASL 2025) - "This retrospective analysis of the FASCINATE-2 Phase 2b trial demonstrated that MR-I can predict MR. In this analysis, MR-I showed potential to predict non-responders. Further analysis and additional non-invasive markers are being pursued specifically at earlier timepoints, to provide non-invasive approaches to predict response to treatment in future MASH clinical studies."

Biomarker • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • FASN

Targeting FASN enhances cisplatin sensitivity via SLC7A11-mediated ferroptosis in cervical cancer. (PubMed, Transl Oncol) - "Targeting FASN enhances cisplatin sensitivity in CC by promoting SLC7A11-mediated ferroptosis. TVB-2640 combined with cisplatin had superior synergistic antitumor effects in cisplatin-resistant CC models."

Journal • Cervical Cancer • Oncology • Solid Tumor • FASN • SLC7A11

AI-based digital pathology shows that denifanstat improves multiple parameters of fibrosis and reduces progression to cirrhosis in MASH patients with F2/F3 fibrosis - results of the FASCINATE-2 study (APASL 2025) - "AI digital pathology results support denifanstat's demonstrated efficacy reducing liver fibrosis and steatosis in MASH. Denifanstat improved fibrosis in peri-sinusoidal and peri-portal zones, consistent with FASN inhibition. The steatosis-corrected algorithm provides further insight into histological effect on liver fibrosis and denifanstat therapeutic benefit."

Clinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis

Pharmacologically targeting fatty acid synthase-mediated de novo lipogenesis alleviates osteolytic bone loss by directly inhibiting osteoclastogenesis through suppression of STAT3 palmitoylation and ROS signaling. (PubMed, Metabolism) - "The results show that ASC40 significantly attenuates bone loss and osteoclastogenesis in both models. In conclusion, our results demonstrate that Fasn-mediated DNL is a novel positive regulator of osteoclastogenesis and may serve as a promising therapeutic target for the treatment of osteoclast-driven osteolytic bone diseases."

Journal • Orthopedics • Osteoporosis • Rheumatology • FASN • FOS • NFATC1 • STAT3

A Study to Evaluate Safety of ASC40 Tablets in Patients with Moderate to Severe Acne Vulgaris (clinicaltrials.gov) - P3 | N=240 | Active, not recruiting | Sponsor: Ascletis Pharmaceuticals Co., Ltd. | Recruiting ➔ Active, not recruiting

Enrollment closed • Acne Vulgaris • Dermatology

Sagimet Biosciences Reports Full Year 2024 Financial Results and Provides Corporate Updates (GlobeNewswire) - "Start-up activities for the Phase 3 program for denifanstat in MASH have begun, with sites activated and patients pre-screened in the fourth quarter of 2024. Screening of patients is expected to start in the first half of 2025...FASCINIT in patients with suspected or confirmed diagnosis of MASLD/MASH: The trial is expected to evaluate the safety and efficacy of denifanstat in this population, with the primary endpoint of safety and tolerability at 52 weeks."

Trial status • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Sagimet Biosciences Reports Full Year 2024 Financial Results and Provides Corporate Updates (GlobeNewswire) - "Start-up activities for the Phase 3 program for denifanstat in MASH have begun, with sites activated and patients pre-screened in the fourth quarter of 2024. Screening of patients is expected to start in the first half of 2025...FASCINATE-3 in patients with F2/F3 (non-cirrhotic) MASH: The trial is expected to evaluate the efficacy and safety of denifanstat in this population, with primary endpoints being liver biopsy assessments at 52 weeks..."

Trial status • Metabolic Dysfunction-Associated Steatohepatitis

Lipid metabolic reprogramming drives triglyceride storage and variable sensitivity to FASN inhibition in endocrine-resistant breast cancer cells. (PubMed, Breast Cancer Res) - "Endocrine resistant breast cancer cells undergo a metabolic shift toward increased triglyceride storage and PUFAs with high degrees of desaturation. While TVB-2640 reduced lipid storage in most conditions, it had limited effects on the growth of endocrine resistant breast cancer cells. Targeting specific lipid metabolic dependencies, particularly pathways that produce PUFAs, represents a potential therapeutic strategy in endocrine resistant breast cancer."

Journal • Breast Cancer • Endocrine Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • ER

Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer. (PubMed, Neoplasia) - "Computational studies with TVB-3166 and TVB-3664, two analogues of the clinical-grade FASNi TVB-2640 (denifanstat), confirmed their uncompetitive behavior towards NADPH when bound to the FASN ketoacyl reductase domain...Experiments in PDAC PDXs in vivo confirmed the synergistic antitumor activity of TVB-3664 with navitoclax and venetoclax, independent of the nature of the replication stress signature of patient-derived PDAC cells. The discovery that targeted inhibition of FASN is a metabolic perturbation that sensitizes PDAC cells to BH3 mimetics warrants further investigation to overcome resistance to mitochondrial apoptosis in PDAC patients."

Journal • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BCL2 • BCL2L1 • BCL2L2 • FASN

Sagimet Biosciences Announces Oral Presentation at the MASH Pathogenesis and Therapeutic Approaches Keystone Symposium (GlobeNewswire) - "Sagimet Biosciences Inc...today announced that an oral presentation on denifanstat’s effect on triglycerides and LDL-cholesterol in advanced fibrosis patients will be delivered at the MASH Pathogenesis and Therapeutic Approaches Keystone Symposium being held February 23-26, 2025 in Banff, Canada. The presentation will feature lipidomic data from a post-hoc analysis of the Phase 2b FASCINATE-2 trial of denifanstat in MASH."

P2b data • Metabolic Dysfunction-Associated Steatohepatitis

Comparison of pharmacological therapies in metabolic dysfunction-associated steatohepatitis for fibrosis regression and MASH resolution: Systematic review and network meta-analysis. (PubMed, Hepatology) - "This study provides updated rank-order efficacy of MASH pharmacological therapies for fibrosis regression and MASH resolution. These data are helpful to inform practice and clinical trial design."

Journal • Retrospective data • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

FASCINATE-3: A Phase 3 Study Evaluating the Safety and Efficacy of Denifanstat in Patients With MASH and F2/F3 Fibrosis (clinicaltrials.gov) - P3 | N=1260 | Not yet recruiting | Sponsor: Sagimet Biosciences Inc. | Initiation date: Dec 2024 ➔ Mar 2025

Trial initiation date • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease